Developmental & Stem Cell Biology

Seeking Regenerative Therapies

The new field of regenerative medicine aims to cure people from within, by restoring or replacing damaged cells. To determine how regenerative medicine might improve the outlook for people with diabetes, investigators in the Section on Developmental and Stem Cell Biology conduct studies of cell biology, gene regulation and molecular signaling pathways.

Although many different cell types contribute to the development of diabetes and its complications, such as heart and eye disease, the most important cells are those in the pancreas, liver, blood vessels, heart, nervous system, kidney and adipose tissue. Understanding how these cell types develop normally will provide insight into how they become damaged or misregulated in people with diabetes. Developmental studies also fuel efforts to use stem cells to provide new sources of tissue—particularly insulin-producing pancreatic islet cells—damaged in patients with diabetes.

Reprogramming Stem Cells

Stem cells may someday provide a “fountain of youth” for diseased tissues. These cells not only have the ability to develop into more than one specialized cell type, but also are capable of dividing to form new cells, creating a self-renewing population. Some stem cells are found in adults, while others exist only in the developing embryo.

Researchers in the section use animal models to understand which genes and molecules create developmental restrictions for different stem cell populations. The ultimate goal is to find a way to reprogram stem cells so that they can develop into mature specialized cells useful for therapy.

Some researchers in the section are investigating the mechanisms that govern the survival and developmental potential of germ cells, which become egg and sperm cells. Germ cells represent the ultimate stem cells because they can develop into any cell in an entire organism. Many of the mechanisms that regulate the development of germ cells also are important for the development of other types of stem cells. Understanding these mechanisms may eventually help make it possible to reprogram adult cells so that they can form new cell types.

To realize the therapeutic potential of stem cells, scientists need to understand the molecular mechanisms that orchestrate cell development and differentiation. Working in a simple model organism (the nematode worm Caenorhabditis elegans), researchers in the section are identifying molecular events that govern digestive system development and function. They expect that these studies will lay the groundwork for future investigations of islet cells and their relevant progenitor cells in humans. Other research in the section focuses on understanding the mechanisms that regulate the function of blood-forming and muscle-forming stem cells. Blood-forming stem cells generate the red and white blood cells necessary to deliver oxygen to body tissues, to ward off infection and to stop bleeding, while muscle-forming stem cells generate muscle fibers needed for controlled contraction of skeletal muscle. Both have important potential applications to the treatment of diabetes.

A major objective of the work on blood-forming stem cells has been to identify mechanisms that control stem cell migration and expansion, with the hope that this knowledge will lead to improved strategies for effective bone marrow transplantation in people with type 1 diabetes. A primary focus concerning muscle-forming stem cells has been to demonstrate their ability to generate functional muscle fibers when transplanted into muscle. This capability might particularly benefit individuals with insulin-resistant type 2 diabetes, in which muscle is a significant insulin-resistant tissue.

Key outcomes include the identification of EGR1, a gene that appears to control blood-forming stem cell replication and migration, the development of new methods for analyzing other cells in the bone marrow that provide critical support for blood-forming stem cell functions, and the demonstration that transplantation of muscle-forming stem cells into the muscle of injured or diseased mice yields many new muscle fibers and helps to restore muscle function.

Preventing Oxidative Stress

Researchers in the section also are seeking to identify novel strategies to protect against oxidative stress, which results when free radicals (natural byproducts of metabolism) become so numerous they damage cells and tissues. Oxidative stress not only influences cell development and function, but also contributes to conditions such as heart disease and cancer. In diabetes, oxidative stress caused by elevated glucose may be the most important underlying cause of long-term complications.

As research at Joslin has shown, elevated glucose during pregnancy causes oxidative stress in the embryo that interferes with the activation of key genes responsible for development. This finding helps to explain why babies born to mothers with diabetes are prone to neural tube defects.

To identify the body’s own protections against oxidative stress, researchers in the section are using the powerful C. elegans model to decode the genetic pathways that are activated to mobilize defenses or block an attack by free radicals. Many naturally occurring antioxidants found in fruits and vegetables bolster these defenses, raising the hope that this research may one day lead to novel therapeutic strategies that harness the body’s own defenses.

Further studies on how glucose affects the antioxidant stress response pathway are now under way with colleagues in the Joslin Section on Vascular Cell Biology. In related studies, they are determining whether stimulation of this oxidative stress resistance pathway may help prevent cell damage by glucose.